• Molecules and Cells
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• 제38권10호
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• pp.886-894
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• 2015

Macrophages are divided into two subpopulations: classically activated macrophages (M1) and alternatively activated macrophages (M2). BCG (Bacilli Calmette-$Gu{\acute{e}}rin$) activates disabled $na{\ddot{i}}ve$ macrophages to M1 macrophages, which act as inflammatory, microbicidal and tumoricidal cells through cell-cell contact and/or the release of soluble factors. Various transcription factors and signaling pathways are involved in the regulation of macrophage activation and polarization. We discovered that BCG-activated macrophages (BAM) expressed a new molecule, and we named it Novel Macrophage Activated Associated Protein 1 (NMAAP1). 1 The current study found that the overexpression of NMAAP1 in macrophages results in M1 polarization with increased expression levels of M1 genes, such as inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-${\alpha}$), Interleukin 6 (IL-6), Interleukin 12 (IL-12), Monocyte chemoattractant protein-1 (MCP-1) and Interleukin-1 beta (IL-$1{\beta}$), and decreased expression of some M2 genes, such as Kruppel-like factor 4 (KLF4) and suppressor of cytokine signaling 1 (SOCS1), but not other M2 genes, including arginase-1 (Arg-1), Interleukin (IL-10), transforming growth factor beta (TGF-${\beta}$) and found in inflammatory zone 1 (Fizz1). Moreover, NMAAP1 overexpression in the RAW264.7 cell line increased cytotoxicity against MCA207 tumor cells, which depends on increased inflammatory cytokines rather than cell-cell contact. NMAAP1 also substantially enhanced the phagocytic ability of macrophages, which implies that NMAAP1 promoted macrophage adhesive and clearance activities. Our results indicate that NMAAP1 is an essential molecule that modulates macrophages phenotype and plays an important role in macrophage tumoricidal functions.

• Molecules and Cells
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• 제42권1호
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• pp.1-7
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• 2019

Macrophage is an important innate immune cell that not only initiates inflammatory responses, but also functions in tissue repair and anti-inflammatory responses. Regulating macrophage activity is thus critical to maintain immune homeostasis. Tyro3, Axl, and Mer are integral membrane proteins that constitute TAM family of receptor tyrosine kinases (RTKs). Growing evidence indicates that TAM family receptors play an important role in anti-inflammatory responses through modulating the function of macrophages. First, macrophages can recognize apoptotic bodies through interaction between TAM family receptors expressed on macrophages and their ligands attached to apoptotic bodies. Without TAM signaling, macrophages cannot clear up apoptotic cells, leading to broad inflammation due to over-activation of immune cells. Second, TAM signaling can prevent chronic activation of macrophages by attenuating inflammatory pathways through particular pattern recognition receptors and cytokine receptors. Third, TAM signaling can induce autophagy which is an important mechanism to inhibit NLRP3 inflammasome activation in macrophages. Fourth, TAM signaling can inhibit polarization of M1 macrophages. In this review, we will focus on mechanisms involved in how TAM family of RTKs can modulate function of macrophage associated with anti-inflammatory responses described above. We will also discuss several human diseases related to TAM signaling and potential therapeutic strategies of targeting TAM signaling.

• Journal of Microbiology and Biotechnology
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• 제32권11호
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• pp.1406-1415
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• 2022

The formation of macrophage foam cells stimulated by oxidized low-density lipoprotein (ox-LDL) is deemed an important cause of atherosclerosis. Transcription factor Yin Yang 1 (YY1), which is a universally expressed multifunctional protein, is closely related to cell metabolism disorders such as lipid metabolism, sugar metabolism, and bile acid metabolism. However, whether YY1 is involved in macrophage inflammation and lipid accumulation still remains unknown. After mouse macrophage cell line RAW264.7 cells were induced by ox-LDL, YY1 and proprotein convertase subtilisin/kexin type 9 (PCSK9) expressions were found to be increased while low-density lipoprotein receptor (LDLR) expression was lowly expressed. Subsequently, through reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blot analysis, Oil Red O staining and cholesterol quantification, it turned out that silencing of YY1 attenuated the inflammatory response and lipid accumulation in RAW264.7 cells caused by ox-LDL. Moreover, results from the JASPAR database, chromatin immunoprecipitation (ChIP) assay, luciferase reporter assay and Western blot analysis suggested that YY1 activated PCSK9 by binding to PCSK9 promoter and modulated the expression of LDLR in the downstream of PCSK9. In addition, the results of functional experiments demonstrated that the inhibitory effects of YY1 interference on ox-LDL-mediated macrophage inflammation and lipid accumulation were reversed by PCSK9 overexpression. To sum up, YY1 depletion inhibited its activation of PCSK9, thereby reducing cellular inflammatory response, cholesterol homeostasis imbalance, and lipid accumulation caused by ox-LDL.

• 대한한의학회지
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• 제30권6호
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• pp.69-79
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• 2009

Objective: In this study, the immunomodulatory activity of a mixture of wild Panax ginseng and red-mold rice extracts (MPR) on RAW 264.7 macrophage cells in the presence and absence of methotrexate (MTX), an anti-cancer drug, was investigated. Methods and Results: In the cell viability, MPR showed a significant cell proliferation and inhibited cell regression by red-mold rice (RMR) alone or MTX alone. MPR induced moderate increase in nitric oxide (NO) production. NO production and inducible nitric oxide synthase (iNOS) mRNA expression by LPS decreased after MPR treatment. In addition, MPR slightly induced COX-2 mRNA expression, but it did not affect the expression of COX-2 mRNA by LPS treatment. In RT-PCR analyses, MPR induced IL-$1{\alpha}$, IL-$1{\beta}$, IL-6, and TNF-$\alpha$ mRNA expression, but had no effect on IL-10 and TGF-$\beta$, regardless of MTX treatment. Furthermore, MPR did not interfere with the cytotoxicity of MTX against MCF-7 human breast carcinoma cells. Conclusions: MPR is efficacious in protecting against MTX-induced cell regression as a result of macrophage activation, resulting in induction of cytokine expression, implying that MPR could be considered an adjuvant in MTX-chemotherapy.

• Toxicological Research
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• 제27권3호
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• pp.167-172
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• 2011

We demonstrate that glycoprotein isolated from Dioscorea batatas (GDB) activates macrophage function. Analysis of the infiltration of macrophages into peritoneal cavity showed GDB treatment significantly increased the recruitment of macrophages into the peritoneal cavity. In order to further confirm and investigate the mechanism of GDB on macrophage activation, we analyzed the effects of GDB on the cytokine expression including IL-$1{\beta}$, TNF-${\alpha}$, and IL-6 in mouse peritoneal macrophages. GDB increased the expression of IL-$1{\beta}$, TNF-${\alpha}$, and IL-6. Cytokine induction by GDB was further confirmed by RT-PCR and ELISA in mouse macrophage cell line, RAW264.7 cells. Treatment of RAW264.7 cells with GDB produced strong induction of NF-${\kappa}B$ DNA binding and MAPK phosphorylation, markers for macrophage activation and important factors for cytokine gene expression. Collectively, this series of experiments indicates that GDB stimulates macrophage activation.

• 약학회지
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• 제46권1호
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• pp.69-74
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• 2002

The effects of genistein on murine thymocytes for inducing apoptotic cell death and phagocytic activity of peritoneal macrophage were studied in vitro. Addition of genistein (10 and 50$\mu$M) to cultured thymocytes from BALB/c mice definitely promoted DNA fragmentation. Also, cytofluorometric analysis of these cells demonstrated a reduction in mitochondrial transmembrane potential ($\Delta$Ψm). But, repeated administration of genistein (1 mg/mouse/day) to mice for 7 days did not cause any detectable DNA fragmentation. Genistein decreased lucigenin chemiluminescence and engulfment of fluorescein-conjugated E. coli particles in peritoneal macrophage. These results suggest that genistein induce an apoptosis of thymocyte via reduction in $\Delta$Ψm and decrease phagocytic activity of peritoneal macrophage in vitro.

• Biomolecules & Therapeutics
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• 제21권6호
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• pp.481-486
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• 2013

Macrophages play a role in innate immune responses to various foreign antigens. Many products from primary tumors influence the activation and transmigration of macrophages. Here, we investigated a migration of macrophages stimulated with cancer cell culture-conditioned medium (CM). Macrophage activation by treatment with CM of B16F10 cells were judged by the increase in protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2). The location where macrophages were at 4 h-incubation with control medium or CM was different from where they were at 5 h-incubation in culture dish. Percentage of superimposed macrophages at every 1 h interval was gradually increased by CM treatment as compared to control. Total coverage of migrated track expressed in coordinates was smaller and total distance of migration was shorter in CM-treated macrophages than that in control. Rac1 activity in CM-treated macrophages was also decreased as compared to that in control. When macrophages were treated with CM in the presence of dexamethasone (Dex), an increase in COX2 protein levels, and a decrease in Rac1 activity and total coverage of migration were reversed. In the meanwhile, biphasic changes were detected by Dex treatment in section distance of migration at each time interval, which was more decreased at early time and then increased at later time. Taken together, data demonstrate that macrophage motility could be reduced in accordance with activation in response to cancer cell products. It suggests that macrophage motility could be a novel marker to monitor cancer-associated inflammatory diseases and the efficacy of anti-inflammatory agents.

• 대한한방부인과학회지
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• 제34권2호
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• pp.1-15
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• 2021

Objectives: This study was designed to examine immuno-modulatory effects of Evodia Rutaecarpine by activating innate immune system and inhibiting inflammation. Methods: First, Cell cytotoxicity was examined with 4T1 breast carcinoma and TG-induced macrophage. To investigate activating innate immune system of Evodiamine Rutacarpine Extract (ERE) on macrophage, we tested tumor necrosis factor-alpha (TNF-α), interleukin-12 (IL-12), and interleukin-6 (IL-6). In addition, TNF-α and nitric oxide (NO) induced by lipopolysaccharide (LPS) were measured after treating with ERE to observe innate immune modulating effect of ERE on RAW 264.7 cell. Also, mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) were examined by western blot analysis. Results: In cytotoxicity analysis, ERE significantly affected tumor cell growth above specific concentration. Also, ERE significantly affected macrophage growth above specific concetration. As compared with the control group, the production of TNF-α, IL-12 and IL-6 were increased in TG-induced macrophage. As compared with the control group, TNF-α and IL-6 were significantly up-regulated in RAW 264.7 cell. The expression of TNF-α and NO induced by LPS after treating ERE was significantly decreased compared with control group. In addition, We observed ERE inhibited the phosphorylation levels of p-extracellular signal-regulated kinase (p-ERK), p-Jun N-terminal kinase (p-JNK), and p-p38 in western blotting by treating ERE on RAW 264.7 cell. Conclusions: ERE seems to have considerable impact on the anti-cancer effect by activation of innate immune system and inflammation control.

• 한국동물학회:학술대회논문집
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• 한국동물학회 1997년도 공동 춘계학술대회
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• pp.79.2-79
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• 1997

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